The clinical trial protocol is identified as version number 1.2 of 23rd of August 2021. It adheres to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) criteria; the SPIRIT Checklist can be found as Additional file 1.
Trial design and blindness
This non-inferiority, prospective, randomized, controlled, single-blind, split-mouth two-group study will be conducted in the pediatric subunits of the Department of Oral Medicine and Surgery of the Strasbourg University Hospital.
The working hypothesis of this study is that hypnosis through virtual reality can reduce children’s anxiety, as well as their pain level during dental care with an efficiency and tolerance at least similar to nitrous oxide inhalation. Specifically, the statistical analyses will be based on an assumption of non-inferiority of VR compared to the pharmacological technique of nitrous oxide sedation.
Each patient (aged from 7 to 10 years old) attends for two visits in order to benefit of 2 similar conservative dental treatments on primary molars.
Everyone was randomly allocated to receive hypnosis through virtual reality or nitrous oxide/oxygen titrated to 50%/50% at the first visit, the alternative being used at the second visit (Fig. 1). This randomization helps avoid any experimental bias related to a first positive or negative experience, each patient being its own control, adjusting for potential confounders.
Vital signs and a video of the child’s behavior are recorded for an external examinator (Fig. 1). The video shows the child’s body response as an indicator for his anxiety level through the procedures. Given the nature of both devices, an open-label protocol is inevitable; the investigator as well as the patient is aware of the device used. To reduce the risk of bias, we propose to hide the child’s face in the treatment videos. Therefore, the external evaluator will be unaware of the device (EMONO or VR) during the assessment of the child’s behavior (Fig. 1). We will also blind the statistician supervising the analyses. It is not possible, however, to blind patients and operators.
a Session using virtual reality goggles; b session using EMONO; c videos viewed by the outcome examinator who can be blinded in order to reduce risks of bias
A pilot study conducted in our department in 2020 focuses on the tolerance and effectiveness of HypnoVR program in our everyday practice and the clinical feasibility of this study protocol. This pilot study primarily includes anxious young patients, aged 7 years and older. It rehearses the recruitment, randomization, allocation, documentation, and sedation procedures according to this protocol. In this phase, eight patients were recruited; however, they will not be included in the group of participants of the final sample.
Involvement in the design of the protocol
No members of the public or patient groups were involved in the design of the protocol.
Randomization
The chosen study design is a crossover study; the experimental design model is split-mouth with both sedations being administered to the same patient during two consecutive treatment sessions. Therefore, the results of the first session may positively or negatively influence the outcome of the second session. After confirming the inclusion criteria, randomization will be conducted to determine the sedation order and teeth to be treated for each session. The first group of children will start treatment with EMONO, while the other group will begin with VR.
Concerning the methodology, randomization will be done using random block sizes with random patient allocation. Utilizing variable block sizes randomly defined with sequence permutation allows for better unpredictability. The risk of investigator anticipation of allocation is minimal since the block sizes vary.
The randomization list will be established by the Group of Methods in Clinical Research of Strasbourg. Randomization will occur via internet, using the Cleanweb platform, after obtaining informed consent during the inclusion visit.
Study population
The participants and dental eligibility criteria are described in Table 1. The patients are referred by their former dentist because the patients experienced dental anxiety during a previous session and could not complete the intervention. Dental exclusion criteria have been chosen to reduce failure that is independent of the treatment studied. No emergency dental care, if needed, is prohibited in children after inclusion in the trial.
Outcomes
The primary outcome of this trial is the assessment of the anxiety levels using the Modified Venham Scale (MVS) and the Face Legs Activity Cry Consolability (FLACC) scale (Tables 2 and 3). Both are standardized hetero-evaluation devices to evaluate the child’s behavior and anxiety level during the procedure. MVS is a scale ranging from 0 (patient completely calm and relaxed) to 5 (patient in distress, completely disconnected) and FLACC ranging from 0 to 8. In our study, the category Face will not be used since the patient’s face is not visible in the video. Several parameters are considered in these scales, such as the child’s movements, crying or screaming, and the ability to perform the procedure. These scales are reliable, easy-to-use, and reproducible tools for evaluating children’s behavior.
Success of the sedation can be defined by the completion of the dental procedure. A Venham score of 3 or more, noted at two different timepoints, requires the end of the session and therefore the failure of the sedation.
The secondary outcomes include:
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Evaluation of analgesia through self-reported pain levels on the Visual Analog Scale (VAS) combined with Wong-Baker’s FACES scale, standardized age-appropriate scales, and through monitoring vital signs during the procedure.
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Assessment of tolerance and response to VR and EMONO through the number and proportion of patients intolerant to VR and pharmacological techniques. Evaluate the proportion of VR or EMONO sessions interrupted (lack of therapeutic continuity). Patients who interrupted VR more than once or refused VR during the intervention session are considered intolerant to VR.
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Assessment of child temperament using a questionnaire and temperament scale (Emotionality Activity Sociability (EAS) questionnaire) [19].
To assess the temperament dimensions of the child, parents complete an Activity, Emotionality, and Sociability (AES) questionnaire with the assistance of an investigator before the care session [19]. The AES questionnaire, which has already been validated in France for children aged 6 to 12 years in 2002 [20], consists of 25 items based on a model of three main dimensions: Activity, Emotionality, and Sociability. Each item has a Likert scale ranging from 1 (extremely untrue, not at all like my child) to 5 (extremely true, exactly like my child) [21].
In addition to the child’s temperament questionnaire, additional questions related to the child’s sociability and artistic and sports development will be proposed to the parents. These questions are aimed at evaluating the impact that extracurricular social, artistic, and sports development has on the child’s cooperation at the dental office.
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❖ Does the child participate in extracurricular activities in a group setting?
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❖ For all extracurricular club activities combined, what is the frequency?
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◦ Less than once a week
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◦ Between 1 and 2 times a week
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◦ More than 2 times a week
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Recruitment procedures
Participants will be recruited in the pediatric subunits of the Department of Oral Medicine and Surgery of the Strasbourg University Hospital. The participant’s timetable is shown in Fig. 2. And the flow chart of the study is shown in Fig. 3.
Schedule of enrolment, interventions, and assessments during the trial
CONSORT flow diagram of recruitment of subjects, randomization, allocation, completion of local anesthesia administration, and analysis
Interventions
During the enrolment, the initial examination is performed by dental students, supervised by a senior practitioner. During the initial consultation, following clinical and radiographic examinations, a diagnosis of the lesions and a treatment plan will be established. Motivation for oral hygiene and dietary habits, as well as prophylactic measures, are carried out. If the study inclusion criteria are met, an information sheet about objectives, methods, follow-up, risks, and restrictions of the trial will be explained and provided to the child and their legal guardians. An appointment will be scheduled with one of the investigators for an informational consultation and consent collection. A minimum reflection period of 1 week will be granted between this initial consultation and the inclusion consultation.
During this second visit, the objectives are to obtain consent after verifying the inclusion and exclusion criteria. It is also important to clearly identify, at this stage, the teeth for which treatment will be scheduled for the study. Then, compliance with oral hygiene and dietary habits are assessed and scaling/polishing and local fluoride application are performed. The “Tell Show Do” psycho-behavioral approach techniques will be used. This approach allows the child to become acquainted with the operating practitioner in a less stressful environment since the procedures are non-invasive. During this session, the investigator will show the child the virtual reality headset equipped with the HYPNO-VR software, which the child can handle and try on to adjust the size of the headset. Subsequently, the child will watch a video presenting various virtual reality scenarios and will choose a universe tailored to their preferences and sensitivity for the intervention session. It is essential for the patient to be able to test the device before the treatment sessions because during the intervention, two of the child’s five senses will be engaged by virtual reality, thus disconnecting them from the external environment (sight and hearing). Common failures of virtual reality found in the literature include refusal to wear the headset. EMONO masks will also be shown to the child, and the size will be chosen based on the child’s face and morphology. The temperament questionnaire will be conducted during this second consultation.
During the treatment sessions, upon the patient’s arrival, vital signs are recorded by the investigator (oxygen saturation and heart rate).
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◦ (T0) The patient is then settled in the treatment room, and sedation can be initiated (T1).
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◦ EMONO session: with a mask tailored to the size of their face and the EMONO debit adjusted to their ventilation rate. The assistant is responsible for monitoring sedation. Verbal reassurance is consistently provided to comfort the child.
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◦ VR session: after adjusting the visual and audio headset on the child’s face, the assistant starts the VR program chosen by the child.
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◦ (T2) Five minutes after induction, intraosseous computerized local anesthesia with the QUICKSLEEPER device is administered. An intraosseous injection of one anesthetic capsule Articaine SEPTANEST 1/200,000 is performed.
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◦ (T3) After placing the dental dam, the investigator proceeds with restorative ± endodontic treatment of the selected primary molar.
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◦ (T4) Once the treatment is completed, sedation is discontinued, and the patient rests in the chair for 5 min.
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◦ (T5) As soon as the investigator deems the child to be back to normal, they can leave the office with their parents.
Throughout the session, video recording of the child’s position and body language is conducted for external evaluation of the child’s behavior during sedation. The Venham score, FLACC score, and vital signs are recorded at T0, T1, T2, T3, T4, and T5.
During the VR session, the patient is first placed in a relaxation room, where a preliminary virtual reality hypnosis sequence aimed at relaxation is initiated for 10 min. This preliminary step before treatment allows the child to become accustomed to the headset and to be prepared for the dental procedure under virtual reality.
The enrollment of participants and the interventions are carried out by a single investigator (N.M.D.) (Fig. 3).
Assessment and calibration of the examinator
An audio/video recording is conducted during the treatment sessions for behavior assessment by a single external examinator. There can be variations in scoring criteria across researchers and even over time by a single researcher.
In order to obtain an objective assessment of anxiety based on the Venham and FLACC scales, prior training and calibration of the external examiner were conducted using a group of 8 patients during the pilot study.
To reinforce the intra-examinator reliability of the tools, video assessment was done twice by the same examinator, at least 5 months apart, and after a second randomization of the videos.
Data management
The baseline data, follow-up trial data, and adverse events will be recorded by operators and evaluators on case report forms (CRFs). Data will be kept anonymous. Patients will be identified by their inclusion data; only the number of the patient and the initial letter of their first and last name will be registered on the CRF.
Determination of sample size
The minimally required number of participants to include was calculated based on the primary outcome (level of anxiety and child behavior during sedation) through simulations. For this purpose, data from various clinical studies were considered to estimate the sample size and the following assumptions were made [22,23,24,25,26]:
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Under pharmacological sedation using EMONO, 30% of subjects will have a Venham score of 2, 50% will have a score of 3, and 20% will have a score of 4.
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30% of subjects will not experience any change in their score.
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Among the subjects who experience a change in their score, 20% will have a decrease of 1 point, 50% will have a decrease of 2 points, and 30% will have an increase of 1 point.
These hypotheses are closed to the hypotheses used to the sample size estimation by Salam et al. (VR group: 2.25 ± 0.89 and control group 3.50 ± 1.31).
A total of 30 subjects will achieve a power of 90% and a type I error rate of 5% to detect a mean score with VR that is not more than 0.1 point higher than the mean score with EMONO.
Statistical analysis
The statistical analysis will consist of both descriptive and inferential parts. Statistical analyses will be conducted using Bayesian methods.
Descriptive statistical analysis of quantitative variables will involve presenting the entire set of observed values (univariate analysis), including the frequency of each value and its relative frequency. These frequencies will be provided individually and in cumulative form. For each variable, measures of central tendency (mean, median), measures of dispersion (variance, standard deviation), and measures of distribution (minimum, maximum, first and third quartiles) will be reported. The normality of the data will be assessed using the Shapiro–Wilk test and quantile–quantile plots. Descriptive analysis of qualitative variables will involve presenting frequencies and proportions of each category in the sample. Cross-tabulations will be provided, including frequencies, row proportions, column proportions, and proportions relative to the total, as necessary.
To address the primary objective, inferential analysis will compare Venham scores between subjects receiving VR and those with EMONO inhalation through paired mean comparisons. For secondary objectives, paired mean and proportion comparisons will be conducted. Bayesian linear regressions will be performed to examine changes in anxiety and pain levels over iterative sessions.
The prior distributions will be minimally informative or informative for sensitivity analysis purposes. For each analysis, the posterior distribution of the parameter of interest (proportion, mean, regression coefficient, etc.) will be estimated using the Markov Chain Monte Carlo method. The default number of iterations will be 100,000 after discarding the first 10,000, retaining every second value (thus, 210,000 iterations will be conducted). Convergence will be assessed graphically, and autocorrelation will be estimated graphically. If necessary, the number of iterations will be increased to reduce autocorrelation.
The analyses will be conducted using the R software in its most current version at the time of analysis, along with any necessary packages, and with the OpenBUGS and JAGS software.
Protocol violations
All protocol violations occurring after randomization will be listed in the clinical report form (CRF) and tabulated by the subject. The final assignment of participants to the per-protocol analysis will be decided at a blinded protocol review meeting before locking the database.
Ethical consideration
The French ethical committee for the protection of persons (Comité de Protection des Personnes (CPP), Sud Méditerranée III) granted approval in September 2021 (2021-A00033-38). The protocol is registered under the IDRCB (2021-A00033-38) with the French National Agency for Medicines and Health Product Safety (ANSM) and on ClinicalTrials.gov (NCT05167331). Any protocol amendments will be justified, submitted to the scientific board, approved by the CPP, and recorded by the ANSM. Updates and modifications will also be logged on ClinicalTrials.gov. Informed consent will be obtained from each eligible child and their legal guardians following a detailed explanation of the trial by an investigator at the respective center. Patients and legal guardians will be informed of their right to withdraw from the study at any time and without explanation or consequences on the follow-up of the patient in the department. Regardless of withdrawal, patients will receive indicated dental treatment in their best interest, with documentation of the withdrawal process. Data confidentiality has been reviewed by the National Committee of Informatics and Freedom (Commission Nationale de l’Informatique et des Libertés (CNIL); reference methodology 001). The database does not contain the first and last names of enrolled patients.
There is no significance level in Bayesian analysis; however, credibility intervals will be calculated at 95% using the quantile method. The effect of a factor will be considered present if the probability that the effect is greater than the reference value is greater than 0.975 or less than 0.025. Non-inferiority can be concluded if the upper limit of the 95% credibility interval for the mean difference of Venham score between VR and EMONO is less than 0.1.
Dissemination of the results
The preparation of manuscripts reporting the results of this RCT will adhere to the Consolidated Standards of Reporting Trials (CONSORT) guidelines [27], and the outcomes will be published in international peer-reviewed journals. The authors of these publications will include individuals involved in developing the protocol, conducting the trial, and writing the manuscript and report. A summary of the study results will be available on ClinicalTrials.gov to ensure broad access to the findings. Data sharing will be conducted at the participant level, and access to the complete protocol can be provided upon request.
Adverse effects
Adverse effects, occurring in approximately 0.5–1.2% of patients after EMONO inhalation, mainly consist of nausea and vomiting. Other potential adverse effects may include oversedation, sweating, dysphoria, restlessness, panic, headache, dizziness, hallucinations, diffusion hypoxia, and expansion of gas-filled spaces. These effects are typically minor and reversible upon discontinuation of inhalation. They can arise during treatment and usually dissipate within minutes after discontinuing inhalation of the mixture [7, 8].
Regarding VR, some individuals (1/4000) may experience dizziness, eye strain, or muscle contractions in response to light stimulation or beams of light. These episodes are more common in children and young adults (Oculus Rift Health and Safety and Warranty Guide). Other signs of discomfort (eye fatigue, altered vision, disorientation, imbalance, coordination difficulties, anxiety attacks, headaches, nausea, vomiting) should prompt discontinuation of VR headset use. These symptoms of VR exposure typically resolve after ceasing headset use [15, 16].
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